Solid Tumors and Biomarkers Program, Center for Applied Medical Research, University of Navarra, Avda Pío XII, 55, 31008 Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IdISNA), 31008 Pamplona, Spain.
Biomolecules. 2021 Oct 18;11(10):1533. doi: 10.3390/biom11101533.
Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors. Given the recent development of small molecule inhibitors of CRMP2 phosphorylation to treat neurodegenerative diseases, our results open the door for their use in cancer treatment.
collapsin 反应介质蛋白 2（CRMP2）是一种衔接蛋白，它将微管蛋白二聚体添加到微管的生长尖端。最初在神经元中描述，现在被认为是一种普遍存在的蛋白质，它干预细胞骨架重塑、突触连接和电压通道运输等过程。越来越多的证据支持 CRMP2 在神经病理学中，以及最近在癌症中发挥重要作用。我们之前描述了 CRMP2 的核磷酸化与肺腺癌患者预后不良之间存在正相关。在这项工作中，我们研究了这种细胞骨架成型蛋白是否参与了癌细胞的迁移。为此，我们使用体外测定和体内共聚焦显微镜评估了肺腺癌细胞迁移过程中 CRMP2 的磷酸化和定位在延伸的细胞膜片中。我们证明了 CRMP2 的组成性磷酸化会损害细胞膜片的形成、细胞黏附和定向迁移。为了寻找这种现象的机制解释，我们发现 CRMP2 Ser522 磷酸模拟突变体显示不稳定的微管聚合物，无法结合 EB1 加-Tip 蛋白和皮质肌动蛋白接头 IQGAP1。此外，整合素回收存在缺陷，这些突变体中的侵袭结构不太明显。重要的是，表达 CRMP2 磷酸模拟突变体的 NSCLC 小鼠异种移植肿瘤的生长明显小于野生型肿瘤。鉴于最近开发了用于治疗神经退行性疾病的 CRMP2 磷酸化小分子抑制剂，我们的结果为将其用于癌症治疗开辟了道路。
